The proposed research uses drug discrimination procedures in monkeys and pigeons treated under different dosing conditions to characterize drugs, particularly novel opioids and opioids that vary in efficacy or receptor selectivity, for their effects in untreated, morphine-treated, and U-50,488-treated subjects. Subjects will discriminate between injections of naltrexone and saline or among injections of naltrexone, saline, and an opioid agonist (etonitazene, morphine or the kappa agonist U50,488). Responding on a naltrexone-associated lever or key will be the behavioral measure of opioid withdrawal, although many of the studies in this proposal are designed to test the range of conditions over which this operational definition of withdrawal is valid. One general hypothesis this proposal is designed to test is whether different degrees of dependence develop as a function of different dosing conditions, and whether such differences in dependence can be characterized quantitatively with drugs that differ in efficacy or with antagonists that bind irreversibly to opioid receptors. These studies will expand the conditions under which antagonist discriminations have been conducted which, in turn, will help define the necessary and sufficient pharmacological conditions for producing an empiricallydefined opioid dependence. These and other theoretical issues (pharmacological and behavioral) are the major thrust of this project. In addition, many of the compounds studied in these experiments are currently used in medicine as analgesics and others are potentially useful as analgesics or for the treatment of drug abuse (e.g., buprenorphine). Assessment of pharmacological activity in morphine-treated rhesus monkeys would appear to be particularly relevant for compounds that might have some utility in the treatment of opioid abuse in humans.